Ophthalmologic biomarkers are measurable ocular features or facets that can be used to detect and assess various pathological and non-pathological conditions affecting a subject. Non-limiting examples of ophthalmologic biomarkers may include pupillary responsiveness (pupil size, pupillary light reflex, pupil motility/kinetics), retinal imagery (retinal blood vessel coloration, retinal blood vessel dimensions, retinal blood vessel architecture, ischemic spots), optical nerve characteristics, exudate appearance, and cellular degeneration. A subject's ophthalmologic biomarkers may reveal a variety of neurological and physiological conditions caused by disease, trauma, and/or exposure to chemical threat agents, see, e.g., U.S. Pat. No. 6,631,989 to Odom et al. Non-limiting examples of trauma and disease may include internal and external traumas, inadequate nutritional status, altered cognitive states, and various congenital, vascular, autoimmune, and connective tissue disorders.
Due to the usefulness of ophthalmologic biomarkers in identifying conditions of interest, various devices and techniques exist for monitoring pupil size and responsiveness characteristics. These systems are generally referred to as pupilometry systems or pupilometers. A variety of pupillary defects are useful in detecting and assessing bilateral afferent or efferent pupillary defects, traumatic injuries to the optic nerve and/or the central nervous system, diseases which affect the central nervous system, and/or conditions caused by exposure to chemical threat agents.
Pupillary size and responsiveness have long been a critical component in clinical assessment of subjects with neurological and physiological conditions. For example, Relative Afferent Pupillary Defect (RAPD), also termed the Marcus-Gunn pupil, is a quantifiable clinical finding that may result from a variety of physiological conditions that affect the retina or optic nerve. In general, RAPD occurs concomitantly with significant optic nerve or retinal disease and/or abnormal condition due to an asymmetrical effect on the two eyes. Diseases or conditions that affect the two eyes symmetrically generally will not be evidenced by RAPD testing. Prominent conditions which may lead to RAPD may include:                Amblyopia with visual acuity of 20/400 or worse;        Cerebral vascular disease;        Optic nerve disorders such as glaucoma, ischemic optic neuropathies, optic atrophy after papilledema, optic neuritis, optic nerve infections/inflammations, optic nerve tumor, orbital disease, and optic nerve damage via radiation, surgery, and other direct insults; or        Retinal causes, such as intraocular tumor, ischemic ocular or retinal disease, retinal detachment, retinal infection, or severe macular degeneration.        
The swinging-flashlight test is widely known and used for evaluating neuro-ophthalmologic defects, and more particularly, RAPD. Briefly, this test is performed in a dimly lit room using a relatively strong, directional light source. Pupillary reactions are observed as the light shines in one eye and then the other in rapid succession. Typically, this swinging back-and-forth between eyes with the light is repeated multiple times until the examiner is confident with respect to the reactivity of the iris/pupil in each eye to both direct and consensual light application. Direct light application means observing the pupillary response in the same eye to which light stimulus is being applied. Consensual light application means observing the pupillary response in the eye opposite to that which is receiving light stimulus.
Normally, when either eye is exposed to direct light, both will constrict. As light shifts from one eye to the other, both pupils begin to dilate, only to re-constrict as the light reaches the opposite eye. In an individual with an afferent lesion, such as in RAPD, shining light into an unaffected eye will cause both pupils to constrict (as normal), whereas shining light into the affected eye will yield a diminished or absent constrictive response in both eyes. Four gradations of this effect can be delineated, and include:                No RAPD (both pupils constrict equally without evidence of pupillary re-dialiation);        Mild RAPD (one pupil shows a weak initial constriction, followed by dilation to a greater size);        Moderate RAPD (one pupil shows sustained constriction, followed by dilation to a greater size); and        Severe RAPD (one pupil shows an immediate dilation to a greater size).        
A byproduct of the swinging-flashlight test is a testing for efferent lesions (oculomotor or pupillary muscle lesions). In this case, a much more readily observable response is noted: one eye maintains its normal direct and consensual pupillary reflex to light, whereas the other pupil shows little or no response to either direct or consensual light stimulation.
There are significant drawbacks associated with the traditional swinging-flashlight test. During visual inspection for RAPD, not only must the examiner swing the visible light quickly between the eyes with substantial consistency to achieve relatively valuable and constant data, the examiner must also rely on his or her subjective opinion as to the starting pupil size and speed of the response to light. Needless to say, the traditional test method involves a considerable degree of subjectivity on the part of the examiner because of the inability to measure pupillary response parameters with precision. Furthermore, the lag time between each eye examination may be problematic since consensual pupillary reflex kinetics is preferably measured at the same time for both eyes.
Disadvantages associated with conventional pupilometers make their use unsuitable for RAPD assessment. Besides the aforementioned challenges, pupilometers lack the ability to measure the response in one eye “relative” to the other. Pupilometers with a binocular-type housing design fair no better. For example, one pupilometer, disclosed in U.S. Pat. No. 6,022,109 to Dal Santo, teaches that binocular pupillary response may be measured by simply flipping the disclosed instrument 180 degree after testing of the first eye is completed. Pupillary response data collected in such manner are of little or no value to a truly accurate diagnosis since they are not measured at the same time and under the same conditions. More importantly, pupilometers lack the means for gathering and assessing other ophthalmologic biomarkers. Conventional pupilometers measure, for example, the diameter of a pupil before and after the pupil is exposed to a light stimulus pulse and the rates at which the pupil may constrict and later dilate in response to the initiation and termination of the light stimulation.
Similarly, various devices and techniques exist for detecting and assessing retinal blood vessel coloration, and are generally referred to as retinal oximetry systems or optical oximeters.
The retina provides the opportunity for non-invasive observation of human microcirculation in vivo. Retinal vasculature can be an indicator for monitoring a range of conditions, including exposure to chemical threat agents, which include various biological toxins and chemical agents such as cyanide and carbon monoxide. In general, exposure to chemical threat agents can drastically affect retinal blood vessel coloration. Specifically, a decrease in the brightness of the retinal arteries can indicate possible carbon monoxide exposure. A significant decrease in the brightness of the retinal arteries can lead to a definitive diagnosis of carbon monoxide exposure. In contrast, an increase in the brightness of the retinal veins can indicate possible cyanide exposure. A significant increase in the brightness of the retinal veins can lead to a definitive diagnosis of cyanide exposure. Numerous congenital, vascular, autoimmune, and connective tissue disorders can initially present with an ocular manifestation. For example, a variety of retinal vascular changes can be seen in hypertensive patients; these depend in part on the severity and duration of the hypertension. Common hypertensive retinal changes are characterized by flame-shaped hemorrhages in the superficial layers of the retina and “cotton-wool” patches caused by occlusion of the pre-capillary arterioles with ischemic infarction of the superficial retina. Chronic hypertension can produce arteriolar sclerotic vacuolar changes, such as copper or silver wiring (light reflection colors) of the arterioles or swelling of the blood vessels near the optic disc. Ocular blood vessels include, but are not limited to: arteries, veins, venules, capillaries, and arterioles.
Retinal imagery may also provide valuable information about neurological health by imaging nerves, including the optic nerve within the eyes.
Significant drawbacks exist with conventional optical oximeters that make measuring retinal blood vessel coloration in emergency situations impractical and inadequate. For example, exposure to organophosphate nerve agents and/or botulinum toxin is not evidenced by the retinal blood vessel coloration test. Moreover, conventional optical oximeters are particularly inaccurate when used to identify early blood loss in trauma victims.
There has been a long sought but unfulfilled need for apparatus, methods and systems that automatically and simultaneously measure and assess ophthalmologic biomarkers in one or both eyes to address the concerns described supra.